Ultrasound image analysis using deep neural networks for discriminating between benign and malignant ovarian tumors: comparison with expert subjective assessment.

OBJECTIVES: To develop and test the performance of computerized ultrasound image analysis using deep neural networks (DNNs) in discriminating between benign and malignant ovarian tumors and to compare its diagnostic accuracy with that of subjective assessment (SA) by an ultrasound expert. METHODS: We included 3077 (grayscale, n = 1927; power Doppler, n = 1150) ultrasound images from 758 women with ovarian tumors, who were classified prospectively by expert ultrasound examiners according to IOTA (International Ovarian Tumor Analysis) terms and definitions. Histological outcome from surgery (n = 634) or long-term (≥ 3 years) follow-up (n = 124) served as the gold standard. The dataset was split into a training set (n = 508; 314 benign and 194 malignant), a validation set (n = 100; 60 benign and 40 malignant) and a test set (n = 150; 75 benign and 75 malignant). We used transfer learning on three pre-trained DNNs: VGG16, ResNet50 and MobileNet. Each model was trained, and the outputs calibrated, using temperature scaling. An ensemble of the three models was then used to estimate the probability of malignancy based on all images from a given case. The DNN ensemble classified the tumors as benign or malignant (Ovry-Dx1 model); or as benign, inconclusive or malignant (Ovry-Dx2 model). The diagnostic performance of the DNN models, in terms of sensitivity and specificity, was compared to that of SA for classifying ovarian tumors in the test set. RESULTS: At a sensitivity of 96.0%, Ovry-Dx1 had a specificity similar to that of SA (86.7% vs 88.0%; P = 1.0). Ovry-Dx2 had a sensitivity of 97.1% and a specificity of 93.7%, when designating 12.7% of the lesions as inconclusive. By complimenting Ovry-Dx2 with SA in inconclusive cases, the overall sensitivity (96.0%) and specificity (89.3%) were not significantly different from using SA in all cases (P = 1.0). CONCLUSION: Ultrasound image analysis using DNNs can predict ovarian malignancy with a diagnostic accuracy comparable to that of human expert examiners, indicating that these models may have a role in the triage of women with an ovarian tumor. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Análisis de imágenes ecográficas utilizando redes neurales profundas para distinguir entre tumores ováricos benignos y malignos: comparación con la evaluación subjetiva de expertos OBJETIVOS: Desarrollar y probar el desempeño del análisis de imágenes ecográficas computarizadas utilizando redes neurales profundas (RNP) para distinguir entre tumores ováricos benignos y malignos y comparar su precisión en el diagnóstico con la de la evaluación subjetiva (ES) por especialistas expertos en ecografía. MÉTODOS: Se incluyeron 3077 (escala de grises, n=1927; power Doppler, n=1150) imágenes de ultrasonido de 758 mujeres con tumores ováricos, que fueron clasificadas prospectivamente por examinadores especialistas en ecografía, de acuerdo con los términos y definiciones de la IOTA (Análisis Internacional de Tumores Ováricos). El resultado histológico de la cirugía (n=634) o el seguimiento a largo plazo (≥3 años) (n=124) sirvieron como el estándar de referencia. El conjunto de datos se dividió en un subconjunto de formación (n=508; 314 benignos y 194 malignos), un subconjunto de validación (n=100; 60 benignos y 40 malignos) y un subconjunto de pruebas (n=150; 75 benignos y 75 malignos). Se utilizó el aprendizaje de transferencia en tres RNP pre-formadas: VGG16, ResNet50 y MobileNet. Cada modelo fue formado primero mediante escalas de temperatura, al igual que los la calibración de los outputs. A continuación, se utilizó una combinación de los tres modelos para estimar la probabilidad de que el tumor fuera maligno con base en la totalidad de las imágenes de un caso determinado. La combinación de RNP permitió clasificar los tumores como benignos o malignos (modelo Ovry-Dx1); o como benignos, no concluyentes o malignos (modelo Ovry-Dx2). Se comparó el desempeño para el diagnóstico de los modelos de RNP, en términos de sensibilidad y de especificidad, con el de la ES para la clasificación de los tumores ováricos en el subconjunto de formación. RESULTADOS: Con una sensibilidad del 96,0%, Ovry-Dx1 tuvo una especificidad similar a la de la ES (86,7% frente a 88,0%; P=1,0). Ovry-Dx2 tuvo una sensibilidad del 97,1% y una especificidad del 93,7%, y designaron un 12,7% de las lesiones como no concluyentes. Cuando se complementó Ovry-Dx2 con ES en los casos no concluyentes, la sensibilidad general (96,0%) y la especificidad (89,3%) no fueron significativamente diferentes de la utilización de ES en todos los casos (P=1,0). CONCLUSIÓN: El análisis de imágenes ecográficas mediante RNP puede predecir el cáncer de ovario con una precisión en el diagnóstico igual a la de los especialistas expertos humanos, lo que indica que estos modelos pueden jugar un papel en el triaje de mujeres con un tumor de ovario. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Phenotypic and genotypic differences between Indian and Scandinavian women with gestational diabetes mellitus.

OBJECTIVE: Gestational diabetes mellitus (GDM) is a transient form of diabetes characterized by impaired insulin secretion and action during pregnancy. Population-based differences in prevalence exist which could be explained by phenotypic and genetic differences. The aim of this study was to examine these differences in pregnant women from Punjab, India and Scandinavia. METHODS: Eighty-five GDM/T2D loci in European and/or Indian populations from previous studies were assessed for association with GDM based on Swedish GDM criteria in 4018 Punjabi Indian and 507 Swedish pregnant women. Selected loci were replicated in Scandinavian cohorts, Radiel (N = 398, Finnish) and STORK/STORK-G (N = 780, Norwegian). RESULTS: Punjabi Indian women had higher GDM prevalence, lower insulin secretion and better insulin sensitivity than Swedish women. There were significant frequency differences of GDM/T2D risk alleles between both populations. rs7178572 at HMG20A, previously associated with GDM in South Indian and European women, was replicated in North Indian women. The T2D risk SNP rs11605924 in the CRY2 gene was associated with increased GDM risk in Scandinavian but decreased GDM risk in Punjabi Indian women. No other overlap was seen between GDM loci in both populations. CONCLUSIONS: Gestational diabetes mellitus is more common in Indian than Swedish women, which partially can be attributed to differences in insulin secretion and action. There was marked heterogeneity in the GDM phenotypes between the populations which could only partially be explained by genetic differences.

ONO-8815Ly, an EP2 agonist that markedly inhibits uterine contractions in women.

OBJECTIVE: To determine the effect of ONO-8815Ly on uterine contractions. DESIGN: A randomised, double-blind, placebo-controlled, dose-ascending, cross-over study. SETTING: Department of Obstetrics and Gynaecology, University Hospital of Lund, Sweden. POPULATION: Seventeen, healthy, parous and permanently sterilised women. METHODS: Intrauterine pressure was recorded on days 1-3 of bleeding of two menstruations. Subjects were intravenously treated with 4 or 8 microg/minute of ONO-8815Ly or placebo for 130 minutes. Intravenous bolus injections of oxytocin, 50 pmol/kg body weight, were given 10 minutes before, during infusion after 60 and 120 minutes and 60 minutes after completion of infusion. The plasma concentrations of ONO-8815Ly were measured in samples obtained immediately before each oxytocin injection. MAIN OUTCOME MEASURE: Area under pressure recording curve (AUC) 10 minutes before and after each oxytocin injection. RESULTS: Twelve women, six in each dose group, completed both recordings. Of these, two women of each group were not included in efficacy analysis due to non-responsiveness to oxytocin or missing baseline value. The AUC over 10 minutes before oxytocin injection after 60 minutes of infusion of ONO-8815Ly at 4 and 8 microg/minute was reduced to 21% and 37% of that before infusion, respectively. The AUC after oxytocin at that time amounted to 21% and 19%, respectively, of that before infusion. The activity and responsiveness remained low after 120 minutes but started to return to baseline 60 minutes after stopping infusion. Placebo had no effect. CONCLUSIONS: ONO-8815Ly is a potent inhibitor of spontaneous uterine contractility in non-pregnant women and it reduces the uterine response to oxytocin injections.

Vasopressin and oxytocin in normal reproduction and in the pathophysiology of preterm labour and primary dysmenorrhoea. Development of receptor antagonists for therapeutic use in these conditions.

Vasopressin and oxytocin are synthesised in the hypothalamus and released to the blood stream via the posterior lobe of the hypophysis. Research during later years has shown that these peptides are also produced in other parts of the brain. The secretion to plasma is stimulated by oestrogen, an effect which is counteracted by progestagen. During delivery the fetus can also produce substantial amounts of vasopressin and oxytocin. Additionally, the uterus itself may be a source of these hormones and we have recently found oxytocin mRNA in the endometrium of non-pregnant women with the highest levels around the time of ovulation. In the onset of labour preterm and at term pregnancy vasopressin and oxytocin are centrally involved and in primary dysmenorrhoea the former hormone seems to play a key role in the mechanisms of increased contractions and reduced blood flow in the uterus of the condition. In women with the latter condition the plasma concentration of vasopressin is several-fold higher than that in healthy control persons. Both in pregnant and non-pregnant women the myometrium is activated via specific vasopressin V1a and oxytocin receptors. This vasopressin receptor is different from the vasopressin V1b receptor of the anterior lobe of the hypophysis, which is important in mood changes and V2 receptor of the kidneys mediating fluid reabsorption. At the onset of labour preterm and at term the vasopressin V1a and oxytocin receptors are elevated to a moderate degree. In non-pregnant women the receptor density varies over the menstrual cycle and increase markedly at the onset of menstruation. Substances, which block the uterine vasopressin V1a and oxytocin receptors inhibit preterm labour and primary dysmenorrhoea.

Effect of SR49059, an orally active V1a vasopressin receptor antagonist, in the prevention of dysmenorrhoea.

OBJECTIVE: To investigate the clinical effect of SR49059 when given shortly before the onset of menstruation as a preventative treatment of dysmenorrhoea. DESIGN: A double-blind, randomised, placebo-controlled, cross-over trial in complete block design (three periods, three treatments). SETTING: A clinical research organisation in Paris, France. PARTICIPANTS: Women aged 18-35 years suffering from primary dysmenorrhoea. INTERVENTIONS: In each of three menstrual cycles, women reported to the study centre and were given a daily dose of either placebo, 100 mg or 300 mg SR49059 from a minimum of 4 hours up to a maximum of three days before the onset of bleeding and/or menstrual pain. If this did not control the pain, women were allowed once a day to take a second dose of study treatment providing that at least 4 hours had passed since the first drug intake. MAIN OUTCOME MEASURES: Intensity of menstrual pain recorded by means of a visual analogue scale. Rating of symptoms of dysmenorrhoea (mainly back and pelvic pain) in relation to functional capacity (Sultan score). Self-assessment of menstrual blood loss in a menstrual diary record. RESULTS: Analysis of intensity of menstrual pain, as recorded by visual analogue scale and Sultan pain score (back and pelvic pain) during the first 24 hours of dysmenorrhoea, showed a dose-related effect of SR49059. The 300 mg dose of SR49059 was significantly more effective than placebo. Similarly, a dose-related effect of SR49059 was shown on total Sultan score. SR49059 was well tolerated and no significant effect on the bleeding pattern was noted. CONCLUSIONS: This study showed for the first time a therapeutic effect of an orally active vasopressin V1a receptor antagonist in the prevention of dysmenorrhoea. Further studies are required to examine effect mechanisms and determine effective doses.

Receptor binding of oxytocin and vasopressin antagonists and inhibitory effects on isolated myometrium from preterm and term pregnant women.

OBJECTIVE: To test binding affinities for, and inhibitory effects on, myometrium of some oxytocin and vasopressin antagonists with respect to their therapeutic potential. DESIGN: Receptor binding studies on transfected cell lines. In vitro contractility studies of human myometrium. SETTING: The Research Laboratory of Sanofi Recherche, Centre de Toulouse, France and the Departments of Obstetrics and Gynecology, Lund University Hospital, Sweden and Bialystok University Hospital, Poland. PARTICIPANTS: Nine women delivered by caesarean section preterm and 37 delivered at term for routine obstetric indications. INTERVENTIONS: The binding affinities of oxytocin, arginine vasopressin, atosiban (1-deamino-2-D-Tyr(OEt)-4-Thr-8-Om-oxytocin), SR 49059 and SR 121463 for the human oxytocin and different subtypes of vasopressin receptors were determined. Concentration-response curves with oxytocin and arginine vasopressin were recorded on myometrium from preterm- and term-delivered women in control experiments and in the presence of 2.5 and 10 nmol/L of SR 49059. Furthermore, using term myometrium, the influence of SR 49059 and SR 121463 in concentrations of 3, 10, 30 and 100 nmol/L on responses to the EC50 concentrations of oxytocin and vasopressin were compared. MAIN OUTCOME MEASURES: Receptor binding affinities. In vitro contractile effects and their inhibitions. RESULTS: Oxytocin had a high affinity for the oxytocin receptor (K(i) in mean = 6.8 nmol/L) and bound, to some extent, to the vasopressin V1a receptor (K(i) = 34.9 nmol/L). Vasopressin displayed higher affinities for vasopressin V1a, V1b and V2 receptors (K(i) = 1.4, 0.8 and 4.2 nmol/L, respectively) than for the oxytocin receptor (K(i) = 48 nmol/L). Atosiban and SR 49059 both had a high affinity for the vasopressin V1a receptor (K(i) = 4.7 and 7.2 nmol/L, respectively, and a moderate one for the oxytocin receptor (K(i) = 397 and 340 nmol/L, respectively). SR 121463 exerted a predominant binding to the V2 receptor (K(i) = 3.0 nmol/L). In the concentration-response experiments levels of up to 10 nmol/L of SR 49059 had no influence on the effect of oxytocin on myometrium from women preterm and at term pregnancy. However, a concentration-dependent inhibition of the responses of both these type of tissues to vasopressin was seen. The effects of EC50 concentrations of oxytocin and vasopressin on term pregnant myometrium were markedly inhibited by 10 nmol/L and higher concentrations of SR 49059, the inhibition of the response to vasopressin being more pronounced than that of the oxytocin response. SR 121463 at maximal concentration only caused slight inhibitions of the oxytocin and vasopressin responses. CONCLUSIONS: Atosiban and SR 49059 both have moderate binding affinities for the human oxytocin receptor and high binding affinities for the vasopressin V1a one. We demonstrated that SR 49059 inhibits the response of term myometrium to oxytocin and that of both preterm and term myometrium to vasopressin. These observations suggest a therapeutic potential of SR 49059 in preterm labour. The vasopressin V2 receptor is apparently not involved to any significant degree in the activation of the pregnant human uterus.

Osmotically-induced release of vasopressin and oxytocin in non-pregnant women--influence of estrogen and progesterone.

BACKGROUND: Circulating vasopressin and oxytocin are influenced by ovarian steroid blood levels, but the effect of estrogen and progestogen treatment on induced release of the posterior pituitary hormones is not clear. METHODS: Eight postmenopausal women who had not been on hormonal replacement therapy for at least two months were included in the study. The women were treated for four weeks with transdermal administration of estradiol-17beta in a daily dose of 100 microg with the addition of 5 mg tablets of medoxyprogesterone twice daily for the last two weeks. A 25 minute intravenous infusion of hypertonic saline (0.06 mg/kg/min) was given before hormonal treatment, and after two and four weeks with serial plasma sampling for assay of vasopressin and oxytocin. RESULTS: The mean basal concentration of vasopressin, which was 0.83+/-0.13 (SE) pmol/L before hormonal treatment, increased to a statistically significant degree after estradiol alone to 1.18+/-0.11 pmol/L and decreased after combined estrogen/progestogen treatment to 0.31+/-0.02 pmol/L. Sodium concentration and osmolality increased in a similar way during all three infusions, but the resultant increase in vasopressin concentration was significantly smaller and slower after treatment with estradiol alone than in the first experiment without pretreatment. The areas under the concentration curve for the second and third infusion were significantly smaller than when no hormone treatment was given. The induced hyperosmolality also caused a rise in oxytocin levels, but no influence of ovarian hormone treatment was observed. CONCLUSIONS: Ovarian hormone administration influences vasopressin secretion, affecting both the basal levels in plasma and the responses to an increase in plasma osmolality. The influence of ovarian hormones on oxytocin secretion is minimal.

Effects of the vasopressin V1a receptor antagonist, SR 49059, on the response of human uterine arteries to vasopressin and other vasoactive substances.

BACKGROUND: Arginine vasopressin (AVP) activates the uterus via V1a receptors and is apparently an important factor for the myometrial hyperactivity, uterine ischemia and pain of primary dysmenorrhea. The orally active and selective, non-peptide AVP1a receptor antagonist, SR 49059, has been shown to inhibit the myometrial action of AVP, but the specific influence of this substance on the effects of AVP and other vasoactive agents on human uterine arteries is unknown. METHODS: Concentration-responses of AVP on isolated medium-sized human uterine arteries were studied after incubation with only vehicle (DMSO, 0.1%) and with SR 49059 in concentrations of 0.5, 2.5 and 10 nmol/L. Furthermore, the concentration-responses of AVP were investigated without and with SR 49059 (2 and 10 nmol/L) on small and medium-sized arteries. Finally, the influence of 2.5 nmol/L of SR 49059 on concentration-responses of endothelin-1, noradrenaline and prostaglandin F2 alpha was studied. RESULTS: The EC50 for AVP on medium-sized arteries was 0.53 +/- 13 nmol/L. SR 49059 caused a competitive, dose-dependent inhibition of AVP-responses, the highest concentration giving an EC50 of 460 nmol/L. The pA2 value was 9.84. The responses of the small artery preparations to AVP, both without and with the antagonist, were more pronounced than those of the medium-sized ones. The vasoconstrictive effects of endothelin-1, noradrenaline and prostaglandin F2 alpha were less pronounced than those of AVP and unaffected by pre-exposure to SR 49059. CONCLUSIONS: The high potency of AVP on human uterine arteries, particularly those of small size, supports an involvement of the peptide in the regulation of uterine blood flow in both physiological and pathophysiological condition. SR 49059 is a potent and selective AVP V1a receptor antagonist in the smooth muscle of human uterine arteries.

[Uterine contractions in non-pregnant women. How are they handled? what is their significance?]. / Livmodersammandragningar hos icke-gravida kvinnor. Hur styrs de? Vilken betydelse har de?

Although myometrial activity in the non-pregnant woman is essential for the expulsion of shed endometrium and blood during menstruation, as well as for the transport of sperms or a newly fertilised ovum, myometrial hyperactivity is associated with primary or secondary dysmenorrhoca. Recordings of intrauterine pressure in non-pregnant women have shown the pattern and propagation of uterine contractions to vary with the phases of the menstrual cycle. The myometrial hyperactivity during dysmenorrhoea and its effect on uterine blood flow have also been clarified. The cyclical variation in myometrial activity is largely the result of the genomic and non-genomic effects of ovarian steroids. Increased secretion of vasopressin and prostaglandin F2 alpha may be an importantaetiological factor involved in the myometrial hyperactivity associated with primary dysmenorrhoea. The effect of vasopressin in the uterus is mediated via the V1 receptor involved in the mediation of its effect in the kidney. Myometrial hyperactivity in non-pregnant women can be regulated by a combination of an oral contraceptive, a prostaglandin synthesis inhibitor and a V1 receptor antagonist.

Effects of SR 49059, an orally active V1a vasopressin receptor antagonist, on vasopressin-induced uterine contractions.

OBJECTIVE: To test the effect of SR 49059, an orally active, nonpeptide, selective and specific antagonist of the vasopressin V1a receptors in humans. DESIGN: A placebo-controlled, double-blind, cross-over trial. SETTING: The Department of Obstetrics and Gynaecology, Lund University Hospital, Sweden. PARTICIPANTS: Twelve healthy women, who had previously been sterilised by tubal ligation. INTERVENTIONS: The women participated on days 1, 2 or 3 of two menstrual cycles, with intrauterine pressure recordings and intravenous bolus injections of 10 pmol/kg body weight of lysine vasopressin given 1 h before and at 1, 2 and 3 h after oral administration of 300 mg of the study drug or of placebo. MAIN OUTCOME MEASURE: The area between the recording curve and zero level of pressure. Vital signs, safety parameters and drug plasma concentrations were also measured. RESULTS: The spontaneous uterine activity as well as the response to lysine vasopressin injections before administration of the test drugs were almost identical at the two experiments. Following intake of SR 49059 the area under the recording curve (0-10 min) after the second, third, and fourth injection of lysine vasopressin were reduced by 57, 42, and 66%, respectively, compared with placebo. Trough plasma concentrations of lysine vasopressin were markedly higher and systolic blood pressure slightly lower after antagonist administration than after placebo, whereas no significant difference between treatments was observed in diastolic pressure, heart rate or plasma osmolality. CONCLUSIONS: This study demonstrates for the first time a biological effect of an orally active vasopressin V1a antagonist in humans in vivo and the results support the importance of vasopressin in uterine activation. The differences between study drug and placebo treatments in lysine vasopressin levels and systolic blood pressure, but lack of difference in osmolality indicate that SR 49059 antagonises the effect of lysine vasopressin on the vasopressin V1a receptor, but not that on the vasopressin V2 one. It is suggested that SR 49059 be explored therapeutically in dysmenorrhoea.

Clinical experience of a combined oral contraceptive with very low dose ethinyl estradiol.

BACKGROUND: The risk of thromboembolic events related to the ethinyl estradiol (EE) dose in oral contraceptive (OC) pills has led to a further dose reduction. METHODS: An OC pill with 150 micrograms desogestrel combined with only 20 micrograms EE was compared with a pill containing the same dose of desogestrel but 30 micrograms of EE in a Scandinavian multicentre study with follow-up visits after 3, 6 and 12 months. RESULTS: In almost 5,000 cycles with each pill the numbers of pregnancies due to method failure with the lower and higher EE dose pills were 0 and 2, respectively. Irregular bleedings were slightly more common with the lower EE dose, but tended to decrease over the year of study. Other side effects were uncommon. Regarding metabolic effects, both pills tended to raise the plasma HDL level and the lower EE dose pill also reduced LDL. Free testosterone was reduced by two-thirds with both pills, showing beneficial effects on acne. CONCLUSIONS: It is concluded that both these pills are reliable and safe, but that many women would accept a slightly greater risk of irregular bleeding with the 20 micrograms EE dose pill in exchange for a reduction in potential risk related to the estrogenic component of OC pills.

PIP: In response to concerns about a possible thromboembolism risk, the ethinyl estradiol dose in oral contraceptives (OCs) has been further decreased. This study compared the effectiveness and metabolic effects of combined OCs containing 150 mcg of desogestrel and either 20 or 30 mcg of ethinyl estradiol. 1000 Swedish women requesting an OC were randomly assigned to receive either the 150/20 or 150/30 formulation, with follow-up visits scheduled 3, 6, and 12 months after OC initiation. The only 2 pregnancies attributable to method failure occurred in the 150/30 group. Although bleeding irregularities were more common in the 150/20 group, this incidence steadily decreased over the 12-month study period. Overall, bleeding irregularities were experienced by 9.9% of the 500 women in the 150/20 group and 6.0% of the 500 in the 150/30 group. The total cholesterol level increased significantly in the 150/30 mcg group but not in the lower-dose group. Low density lipoprotein cholesterol decreased only among 150/20 OC users. Total triglycerides increased more in users of the 30 mcg pill. Both pills reduced free testosterone levels substantially, but to the same extent. The small percentage of women who experience irregular bleeding with the lowest-dose OC are likely to accept this discomfort in exchange for its potentially improved safety profile.

Fibromyomas and uterine contractions.

BACKGROUND: Women with uterine fibromyomas may suffer from dysmenorrhea, menorrhagia or infertility, which all may be due to an effect of the fibroids on uterine activity. The effect of myomectomy on uterine contractility is unknown. METHODS: In women undergoing myomectomy because of dysmenorrhea, menorrhagia or infertility, intrauterine pressure was recorded before and three months after the operation on corresponding days of the menstrual cycle. Records were obtained during spontaneous uterine activity as well as after oxytocin and vasopressin challenge by intravenous bolus injections of 10 pmol/kg body weight. The area under the recording curve (AUC), maximal amplitude of uterine contractions and deformation index of uterine pressure recordings were measured. RESULTS: In six women, in whom recordings could be obtained before and after operation on corresponding days of late follicular phase of the menstrual cycle, the AUC and maximal amplitude of contractions increased after myomectomy. The effect of oxytocin injection also varied, whereas no difference was seen in effect of vasopressin. CONCLUSIONS: It is suggested that women with uterine fibromyomas may have disturbed uterine spontaneous contractions and responsiveness, which may be regulated by myomectomy.

Effect of the non-peptide, vasopressin V1a receptor antagonist, SR 49059 and its enantiomer, SR 49770, on isolated human myometrium.

BACKGROUND: Vasopressin seems to be an important etiological factor for the myometrial hyperactivity and reduced blood flow in primary dysmenorrhea. Substances which block the action of vasopressin on the uterus are therefore of interest. METHODS: The effect of an orally active, non-peptide vasopressin V1a receptor antagonist, SR 49059, as well as its enantiomer, SR 49770, which is 50 to 100 fold less potent in binding studies, were tested in vitro on myometrium from 14 subjects. Two doses of the compounds, 2 nmol/L and 10 nmol/L, were used for counteracting the contractile effect of arginine vasopressin in a concentration of 0.7 nmol/L. RESULTS: SR 49059, in the lower concentration, significantly decreased the response to arginine vasopressin, measured as area under the recording curve, to 48 per cent of that to the agonist alone, and in the higher dose to 28 per cent. SR 49770 was much less potent in reducing the response to vasopressin. CONCLUSION: The myometrial action of arginine vasopressin is exerted via V1a receptors. The potent stereospecific inhibitory effect of SR 49059 on arginine vasopressin-induced myometrial activity indicates that the compound acts specifically through V1a receptors and may have a therapeutic potential in primary dysmenorrea.

Receptor-mediated uterine effects of vasopressin and oxytocin in nonpregnant women.

OBJECTIVE: To study in nonpregnant women myometrial actions of vasopressin and oxytocin and the involvement in these effects of specific uterine receptors. SUBJECTS: Twenty-eight women undergoing hysterectomy for benign gynaecological disorders. INTERVENTIONS: Intrauterine pressure recordings. Intravenous bolus injections of 10 pmol/kg body weight of vasopressin and oxytocin. Repeated blood sampling for measurement of vasopressin and oxytocin concentrations in plasma. Recording of effects of vasopressin and oxytocin on isolated myometrium. Estimation of myometrial concentrations of vasopressin V1a and oxytocin receptors. Measurement of plasma oestradiol and progesterone. MAIN OUTCOME MEASURES: Vasopressin- and oxytocin-induced increases of the area under the in vivo recording curve over 10 minutes and EC50 concentrations of dose-responses in vitro. Concentrations of vasopressin V1a and oxytocin receptors. RESULTS: Vasopressin was on average four times more potent than oxytocin in vivo. The effect of vasopressin premenstrually was more pronounced than in women under oestrogen influence only (proliferative phase-hyperproliferation; P = 0.02), and tended to be more marked than in those in the luteal phase (P = 0.07). No significant variation in oxytocin response with the hormonal state was observed. EC50 concentrations of vasopressin were more than 20 times lower than those of oxytocin. The median concentration of the vasopressin V1a receptor was 208 (range 139-343) fmol/mg protein and that of the oxytocin receptor 49 (38-87) fmol/mg protein. Vasopressin receptor concentrations and in vivo effects of this peptide did not correlate, whereas for those of oxytocin a significant correlation was observed (P = 0.02). CONCLUSION: The high potency of vasopressin in nonpregnant women, particularly premenstrually, firmly supports an aetiological importance of this peptide in the uterine hyperactivity of primary dysmenorrhoea. Oxytocin seems to be less important in this condition in view of its much smaller potency and the absence of increase in effect premenstrually. Vasopressin appears to influence both the oxytocin and the vasopressin V1a receptor sites in the uterus, whereas oxytocin acts specifically on its own receptor.

Circulating oxytocin and vasopressin is influenced by ovarian steroid replacement in women.

BACKGROUND: The posterior pituitary hormones appear to be involved in the etiology of primary dysmenorrhoea, but mechanisms regulating their release, particularly the influence of ovarian steroids, are not fully understood. METHODS: The effect of 17 beta-estradiol and medroxyprogesterone alone and in combination on oxytocin and vasopressin levels was therefore studied in 10 postmenopausal women. RESULTS: Transdermal treatment with estradiol alone by means of patches in a dose of 100 micrograms/24 h for five days resulted in an elevation of the mean plasma concentration of this hormone from undetectable to 262 pmol/l and increase in mean circulating levels of vasopressin from 0.82 to 1.22 pmol/l and of oxytocin from 2.50 to 3.98 pmol/l. Oral administration of medroxyprogesterone in a dose of 10 mg per day for 5 days, which resulted in a mean plasma level of 4.3 nmol/l, suppressed vasopressin concentrations to 0.60 pmol/l. When given after five days of treatment with estradiol, medroxyprogesterone also antagonized the stimulatory effect of the estrogen on vasopressin secretion. Medroxyprogesterone alone increased the plasma oxytocin concentration to 3.26 pmol/l, but the progestogen did not significantly influence the stimulatory effect of estradiol on oxytocin secretion. CONCLUSIONS: It is concluded that posterior pituitary hormone secretion is influenced by estradiol and progestogens, and that this may be a mechanism for the involvement of ovarian hormones in the etiology of primary dysmenorrhoea.

Effects of cadmium on myometrial activity of the nonpregnant human. Interactions with calcium and oxytocin.

With respect to recent reports suggesting an involvement of cadmium in preterm labor, the effects of this ion on the activity of myometrial strips from term pregnant women were examined. The interactions of cadmium with calcium and oxytocin on myometrial activity were also studied. Cadmium alone inhibited spontaneous contractile activity already in a concentration of 10(-9) M and in 10(-3) M myometrial contractions were almost completely abolished. Responses to Ca2+ and oxytocin were significantly increased by exposure to cadmium in low concentration (10(-9) M-10(-8) M), whereas higher concentration of Cd2+ had inhibitory action. These results suggest that cadmium not only blocks Ca2+ channels in the human myometrium, but also interferes with intracellular mechanisms involved in excitation-contraction coupling. The increased responses to Ca2+ and oxytocin in the presence of low amounts of Cd2+ support a role of cadmium in mechanisms of preterm labor.